Enantioselective Intermolecular C-O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst

Article abstract of DOI:10.1021/jacs.7b11197

We report a series of enantioselective C-O bond cross-coupling reactions based on remote symmetry breaking processes in diarylmethine substrates. The key to the chemistry is multifunctional guanidinylated peptide-based ligands that allow highly selective,

Full text of DOI:10.1021/jacs.7b11197

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Article
Enantioselective Intermolecular C–O Bond Formation in the Desymmetrization
of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst
Alex J. Chinn, Byoungmoo Kim, Yongseok Kwon, and Scott J. Miller
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11197 • Publication Date (Web): 08 Nov 2017
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Page 1 of 8
Journal of the American Chemical Society
Enantioselective Intermolecular C–O Bond Formation in the
Desymmetrization of Diarylmethines Employing a Guanidinylated
Peptide-Based Catalyst
Alex J. Chinn, Byoungmoo Kim, Yongseok Kwon and Scott J. Miller*
Department of Chemistry, Yale University, P.O-Box 208107, New Haven, Connecticut 06520-8107, United States
Supporting Information Placeholder
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ABSTRACT: We report a series of enantioselective C–O bond cross-coupling reactions based on remote symmetry breaking processes in
diarylmethine substrates. Key to the chemistry are multifunctional guanidinylated peptide-based ligands that allow highly selective, intermolecular
Cu-catalyzed cross-coupling of phenolic nucleophiles. The scope of the process is explored, demonstrating efficiency for substrates with a range of
electronic and steric perturbations to the nucleophile. Scope and limitations are also reported for variation of the diarylmethine. While the presence
of an intervening tBu-group is found to be optimal for maximum enantioselectivity, several other substituents may also be present such that
appreciable selectivity can be achieved, providing an uncommon level of scope for diarylmethine desymmetrizations. In addition, chemoselective
reactions are possible when phenolic hydroxyl groups within substrates that contain a second reactive site, setting the stage for applications in diverse
complex molecular settings.
Introduction
(a) Cai and Co-workers:
Ligands
R'
OH
R
Enantioselective cross-coupling reactions have become an established
method for synthesizing chiral compounds. The most prevalent
examples involve the formation of C–C bonds to generate point or
axial chirality.1 The creation of stereogenic C–O bonds by cross-
coupling, in comparison, is under developed. In fact, the only presently
reported examples are intramolecular.2 For example, Cai recently
reported the elegant desymmetrization of 1,3-diols with this approach.3
Beaudry also described a fascinating atroposelective Cu-catalyzed
macrocyclization (Figure 1a) wherein an axis of chirality was set due to
hindered bond rotation about the diarylether.4 The design of new
asymmetric C–O bond-forming reactions must take into consideration
the divalency of the O-atom involved. That is, on its own the O-atom is
not necessarily a stereogenic center. However, C–O bond forming
Y
Cu/Ligand
Y
NH
NH
OH
OH
X
O
R
R
81-95% yield
up to 98:2 er
X = I or Br
Y = empty, CH2, or O
Beaudry and Co-workers:
O
Cu/Ligand
O
CO2H
MeO
Br
N
MeO
O
Me
HO
39% yield
72:28 er
MeO
OMe
Me
Me
Me
Me
(b)
Me
Me
O
O
O
Peptide Catalyst
CHCl3, -30 °C
+
O
*
Me
Me
HO
OH
HO
O
Me
2
1
80% yield
95% ee
cross-coupling reactions may be enantioselective in
a broader
molecular context. For example, in addition to the symmetry-breaking
reactions of Cai, we showed that remote functionalizations such as the
reaction of 1 to give 2 (Figure 1b) can also create a stereogenic center.5
We now report in this study a family of reactions that combine the
unusual situation of enantioselective C–O bond forming cross-
coupling reactions within the also challenging context of remote
asymmetric induction. Herein, we describe symmetry-breaking
reactions of diarylmethines such as 3 to give chiral diarylethers like 4
with significant levels of enantiocontrol (Figure 1c). These reactions,
to the best of our knowledge, represent the first reports of metal-
catalyzed, enantioselective C–O bond cross-coupling that involve
intermolecular reactions.
Me
Me
Ligand
Me
(c)
OH
Me
HN
R
Me
O
O
O
[Cu/Ligand]
F3C
N
H
N
H
CF3
N
O
HN
Br
Br
Me
O
3
O
Li
O
Me2N
Me2N
O Me
Me
Me
N
Me
O
L14
H
O
O
- Up to 68% yield and 99:1 er
- Subtle peptide/substrate interactions
- Broad phenol scope
- Chemoselective for phenolic
nucleophiles
F3C
N
H
N
H
CF3
O
Br
4
R
Figure 1. (a) Precedent for enantioselective intramolecular C–O bond
forming cross-coupling. (b) Enantioselective acylation of bis(phenol)
with remote, enantiotopic sites. (c) Present study: Desymmetrization
through remote Cu-catalyzed cross-coupling for intermolecular C–O
bond formation.
We chose to pursue these reactions for the synthesis of unsymmetrical
diarylmethine compounds, in part due to their relevance as
pharmacological agents.6 In addition, they provide scaffolds to explore
reactions that break symmetry in mechanistically distinct ways.7 One
type of diarylmethine desymmetrization reaction involves bond
formation proximal to the pro-stereogenic methine center, wherein a
catalyst interacts explicitly with the pro-chiral center.8 Oftentimes,
these elegant processes possess a requirement for a directing group (eq
1a), or other specific substituent such as a silyl ether at the intervening
prostereogenic center (eq 1b).9 Even in rare cases where the
intervening prostereogenic center is varied (eq 1c), proximal
functionalization is the norm.10 When the enantiotopic site is further
removed from the pro-chiral center and when it lacks the
obvious potential to serve as a catalyst-ligating functional group, it
becomes less intuitive how a chiral catalyst might differentiate among
the enantiotopic sites. Nonetheless, one strategy that has emerged for
the enantioselective synthesis of these molecules is catalytic
desymmetrization, wherein peptide-based catalysts are employed to
achieve remote site-differentiation. In addition to the organocatalytic
acylation of diarylmethinyl bis(phenol) 1 shown in Figure 1b,5 we
recently showed that desymmetrization of 3 was possible through
copper-catalyzed cross-coupling of malonyl nucleophiles when
guanidinylated peptides such as L1are used as ligands (eq 2).11 As we
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Page 2 of 8
show below, exploration of the complementary C–O bond forming
desymmetrization reveals a
revealed side products of the reaction to be 7 and 8 (eq 3); each
1
2
3
4
5
6
7
8
seemed to originate from small amounts of water in the reaction
mixture, which could either serve as the cross-coupling
Table 1. Initial Optimizationa
Yu and Co-workers:
Ligand
OH
O
1.1 equiv
H
N
N
Pd/Ligand
O
N
H
H
H
R
(1a)
Me
Me
Me
Me
Menthyl(-)
OH
Me
Me
Me
MeO
RB(OH)2
O
5 mol% Cu(MeCN)4BF4
10 mol% L1
O
O
O
O
Me
50-91% yield
54-95% ee
Base
F3C
N
N
CF3
Solvent, Temp, 15 h
F3C
N
N
CF3
H
H
H
H
Ligand
Me
Br
Br
R
R'
Hartwig and Co-workers
OSiEt2H
O
3
Me
4a, R' = Br
6a, R' = R
R =
O
SiEt2
Rh/Ligand
9
PPh2
Me
MeO
(1b)
*
R
R
R
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
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35
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58
59
60
3
4a
6a
erc
% Yieldb
Entry
1
Solvent
Temp. (°C)
rt
Base (equiv)
% Remainingb
% Yieldb
Ph2P
S
54-90% yield
72-99% ee
Cs2CO3 (3.2)
DMF/Tol (1:2)
68
26
0
89:11
Me
Cramer and Co-workers
Cs2CO3 (3.2)
Cs2CO3 (3.2)
Cs2CO3 (3.2)
Cs2CO3 (3.2)
Cs2CO3 (3.2)
Cs2CO3 (3.2)
2
3
4
5
6
7
Tol
DCM
rt
rt
rt
rt
rt
rt
rt
98
100
98
77
85
70
0
0
0
0
0
0
0
0
n/a
n/a
Ligand
R4
R1
Br
Dioxane
DMF
0
n/a
N
O
Ph
Ph
Me
H
Pd/Ligand
(1c)
18
9
85:15
90:10
83:17
R3
H
O
R1
O
O
Me
Me
R3
THF
R2N
O
P
NMe2
O
MeCN
22
Ph
Ph
R4
R4
R4
K3PO4 (3.2)
K2CO3 (3.2)
K3PO4 (3.2)
K3PO4 (3.2)
K3PO4 (3.2)
K3PO4 (4.0)
K3PO4 (4.0)
K3PO4 (4.0)
K3PO4 (4.0)
8
DMF/Tol (1:2)
DMF/Tol (1:2)
DMF/Tol (1:2)
DMF/Tol (1:2)
DMF/Tol (1:2)
MeCN
76
100
72
40
12
60
35
31
16
22
0
0
0
92:8
n/a
78-99% yield
8-95% ee
9
rt
Previous Studies:
O
10
11
12
13
14
15
16
40
60
80
40
45
50
60
33
45
40
30
56
55
59
91:9
91:9
91:9
90:10
91:9
91:9
92:8
1
3
O
O
t-Bu
Ligand
HN
EtO
OEt
O
O
12
2
Me
Me
[Cu/Ligand]
F3C
N
H
N
H
CF3
O
Br
Br
Br
3
MeCN
5
N
(2)
O
O
t-Bu
MeCN
6
O
Li
MeCN
12
O
O
Me2N
Me2N
N
F3C
N
H
N
H
CF3
aReported results are the average of two trials. Reaction conditions: 3
(0.2 mmol), 4-methoxyphenol (1.1 equiv), Cu(MeCN)4BF4 (5 mol
%), peptide (10 mol %), base (see above), and solvent (0.8 mL). bYield
was determined using 1H NMR by comparing to an internal NMR
standard (1,4-bis(trimethylsilyl)benzene). cEnantiomeric ratios were
determined using chiral HPLC analysis. The absolute configuration is
currently unknown and enantiomers of 4a are drawn arbitrarily.
O
H
EtO
OEt
5
L1
74% yield
92:8 er
O
O
surprising generality of the guanidinylated peptide ligands. Notably,
this class of ligand had not been reported for transition metal catalysis
prior to our initial study. Several critical facets of this new study are: (a)
subtle but significant features within the peptide-based ligand such as
the length and stereochemical array of the peptide, (b) generality of the
oxygen nucleophile that may be employed, including reasonable
tolerance of steric bulk, (c) appreciable scope, but also some
documented limitations, for substituents on the intervening pro-
stereogenic carbon atom of the diarylmethine, (d) reliable
chemoselectivity for phenol-based functionality in substrates that
possess more than one O-based nucleophilic site, and (e) O-selectivity
partner (i.e., to give 7) or as a hydrolytic agent (i.e., to give 8).12
Indeed, when reactions were deliberately carried out in the presence of
H2O (10 equiv) notable quantities of phenol 7 and aniline 8 were
observed (eq 3). Gratifyingly, conducting the reactions in MeCN with
rigorous exclusion of moisture at elevated temperatures resulted in
cleaner reactions such that good conversions to 4a could be obtained,
without loss of enantioselectivity (Table 1, entries 13–16). For
example, when the reaction was conducted at 60 °C, 4a could be
over potentially competitive N-reactivity within
a bifunctional
substrate.
observed in 59% with 92:8 er (entry 16).
Me
Me
Me
Results and Discussion
O
O
Me
Me
F3C
N
N
CF3
Me
Initial optimization. We began our studies with reaction conditions
that were previously shown to be successful in the desymmetrization of
3 through C–C bond formation. These proved a useful starting place,
as we observed modest conve- rsion to the desired mono-coupled
product 4a, with good enantioselectivity at room temperature (Table
1, entry 1; 26% conv., 89:11 er). We then confirmed through a solvent
screen that a DMF/Tol solvent mixture was more effective than other
solvents in terms of promoting the enantioselective formation of 4a.
For example, the reaction did not proceed in toluene, DCM or dioxane
at room temperature, and lower conversions were observed in DMF,
THF and MeCN (Table 1, entries 2–7). Variation of the base revealed
that K3PO4 led to slightly higher enantioselectivity (Table 1, entry 8;
92:8 er), while K2CO3 resulted in no reaction (Table 1, entry 9). We
then learned that the reaction could deliver higher levels of conversion
to 4a without significant loss in enantioselectivity through conducting
the reaction at elevated temperatures (Table 1, entries 10–12; up to
45% conv., 91:9 er). However, careful analysis of the reaction mixtures
10 equiv H2O
H
H
OH
Br
5 mol% Cu(MeCN)4BF4
7, 7%
10 mol% L1
Me
O
O
(3)
Me
Me
3.2 equiv K3PO4
CF3
DMF/Tol, 60 °C, 15 h
+
F3C
N
N
H
H
O
Br
Br
3
H2N
N
CF3
63% remaining
H
Br
Br
8, 4%
Peptide Optimization Various additional aspects of optimization
were carried out, culminating in reactions conducted at 45 °C, in
MeCN with 1.1 equiv of nucleophile relative to 3, and catalyst loading
of 10 mol % (1:2, Cu/ligand).13 Among the most interesting aspects of
these studies was the evaluation of different peptide-based ligands
(Table 2). These studies were driven by hypotheses that built on
earlier observations in the catalysis of C–C bond forming cross-
coupling reactions. As shown in Figure 2, our thinking about the
attributes of guanidinylated peptides in Cu-catalyzed cross-coupling
builds upon models wherein the nature of the C-terminus of the
peptide proved critical for ensuring communication between the
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catalyst and substrate through a distal interaction with the remote
(Table 2, entries 12–15) afforded higher levels of enantioselectivity
arene ring and a cationic species such as Cs+ or K+.11 Given the new
than any other length of peptide that we examined, and we settled upon
these for further studies. Intriguingly, these tetrapeptide ligands
demonstrated an unusual insensitivity to the identity of the i+3 residue.
Peptides L12 and L13 (Table 2, entries 12–13), which contain
opposite enantiomers of the alanine residue at the i + 3 residue,
perform nearly identically in the reaction (~61% yiled by NMR, 96:4
er). This result is particularly interesting given that heterochirality
between a defined secondary structures which in turn can affect
catalysis.14,15 This result is perhaps more striking when compared with
L11, which demonstrates the importance of the i residue’s stereo-
configuration. Varying this stereocenter reversed enantioselectivity
relative to epimeric ligand L10, in addition to a reduction in the
absolute selectivity with an er value of 34:66 (Table 2, entry 11). Based
on this result, it seems that heterochirality between the i and the i+1
position is important for effective catalysis. Other substitutions at the
i+3 position also provided 4a with good yields (Table 2, entries 12-15),
and high enantioselectivity. Ultimately, L14 was selected as the
premier ligand for the remaining experiments, given that the level of
conversion to the desired mono-coupled product 4a is higher than
other tetrapeptide catalysts. the i+1 and the i+3 residue often biases
peptide sequences towards a defined secondary structures which in
turn can affect catalysis.14,15 This result is perhaps more striking when
compared with L11, which demonstrates the importance of the i
residue’s stereo-configuration. Varying this stereocenter reversed
enantioselectivity relative to epimeric ligand L10, in addition to a
reduction in the absolute selectivity with an er value of 34:66 (Table 2,
entry 11). Based on this result, it seems that heterochirality between
the i and the i+1 position is important for effective catalysis. Other
substitutions at the i+3 position also provided 4a with good yields
(Table 2, entries 12-15), and high enantioselectivity. Ultimately, L14
was selected as the premier ligand for the remaining experiments, given
that the level of conversion to the desired mono-coupled product 4a is
higher than other tetrapeptide catalysts.
1
2
3
4
5
6
7
8
reaction media for the enantio-
Me
Me
Me
M
Peptide Optimization Hypotheses
O
Br
* Suitable peptide lengthÆ C-terminus
interacts with distal arene ring
N
N
F3C
Br
O
M
O
O
CF3
[Cu]
O
O
O
* Matched stereogenic centers Æ
maximize enantioselectivity
N
O
N
Me2N
Me
Me
N
NMe2
H
9
Figure 2. Proposed Catalyst and Substrate Interactions
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
selective C–O bond formation, we speculated that the peptide ligands
could adopt different secondary structures that effect the distal cation-
p interaction and, ultimately, enantioselectivity. As such, our ligand
screen was designed to assess (a) a suitable peptide length for ensuring
optimal interactions, and (b) explore stereochemical arrays within the
peptide sequence to achieve maximum levels of enantioselectivity. Of
all of the i+2 residues examined (Table 2, entries 1–6),
aminoisobutyric acid (Aib) was found to be optimal both in 2, entries
1–6), aminoisobutyric acid (Aib) was found to be optimal both in
terms of reactivity and enantioselectivity (65% conv., 94:6 er. Table 2,
entry 1). This finding is consistent with our observations from previous
studies. However, in contrast to those studies, peptides with –OMe
and –NHMe C-terminal caps showed comparable enantioselectivity
values to peptides with a C-terminal carboxylate (Table 2, entries 7–8).
These catalysts appear to be more active than carboxylate-based
catalysts as they lead to a higher total level of conversion, when
considering the sum of mono- and di-coupled products, which likely
impacts the observed er value. This possibility will be discussed further
below (Scheme 1).
While examining the effect of peptide length on catalytic activity, it was
found that the truncated dipeptide ligand L9 (Table 2, entry 9)
demonstrated
a notable decrease in enantioselectivity, while the
Kinetic Resolution Studies. During these studies, it became apparent
that er values were conversion dependent in part due to a
elongated pentapeptide ligand L10 (Table 2, entry 10) showed similar
selectivity to L1 (Table 1, entry 1). However, tetrapeptide ligands
Table 2: Optimization of Peptide Sequence and Lengtha
i+2
OH
1.1 equiv
R
R1
Me
Me
Me
Me
Me
Me
HN
O
Me
Me
MeO
Me
i+1
O
10 mol% Cu(MeCN)4BF4
20 mol% Ligand
N
HN
i +3
R2
O
O
O
O
O
O
+
O
i
4.0 equiv K3PO4
MeCN, 45 °C, 15 h
F3C
N
N
CF3
O
O
F3C
N
N
CF3
Me2N
Me2N
F3C
N
N
CF3
NH
H
H
H
H
H
H
Br
Br
O
Br
O
O
i+4
N
R3
O
3
4a
6a
H
O
MeO
R4
MeO
OMe
Ligand
3 % Remainingb
4a %Yieldb
6a % Yieldb
erc
Entry
Ligand
i
i+1
i+2
i+3
i+4
1
2
3
4
5
6
7
8
9
L1
L2
TMG-Asp
TMG-Asp
TMG-Asp
TMG-Asp
TMG-Asp
TMG-Asp
TMG-Asp
TMG-Asp
TMG-Asp
TMG-Asp
Aib-OLi
-
16
23
19
22
27
21
6
65
62
61
62
58
60
52
59
58
60
13
8
94:6
93:7
92:8
92:8
93:7
93:7
95:5
95:5
90:10
94:6
D
-Pro
-Pro
-Pro
-Pro
-Pro
-Pro
-Pro
-Pro
-
-
-
-
-
-
-
-
-
Cle-OLi
-Ala-OLi
-
D
D
D
D
D
D
D
L3
-
11
9
D
L4
Gly-OLi
Acpc-OLi
Ala-OLi
Aib-OMe
Aib-NHMe
-
-
L5
-
6
L6
-
8
L7
-
18
20
6
L8
-
9
L9
-
29
23
D
-Pro-OLi
10
11
L10
L11
L12
L13
L14
L15
Aib
D-Ala-OLi
9
D
-Pro
D
-Ala
-Ala
TMG-D-Asp
TMG-Asp
Aib
Aib
D-Ala-OLi
-
27
15
57
61
15
9
34:66
96:4
D
-Pro
-Pro
D
12
13
14
15
D
D
-Ala-OLi
TMG-Asp
TMG-Asp
TMG-Asp
Aib
Aib
Aib
Ala-OLi
-
-
-
13
13
15
61
67
65
9
8
9
96:4
96:4
96:4
D
D
D
-Pro
-Pro
-Pro
D
-Leu-OLi
D
-Phe-OLi
aReported results are the average of two trials. Reaction conditions: 3 (0.2 mmol), 4-methoxyphenol (1.1 equiv), Cu(MeCN)4BF4 (10 mol %), peptide (20 mol %),
K3PO4 (4.0 equiv), and MeCN (0.8 mL), 45 °C bYield was determined using 1H NMR by comparing to an internal NMR standard (1,4-bis(trimethylsilyl)benzene).
cEnantiomeric ratios were determined using chiral HPLC analysis. dAbbreviations: TMG, tetramethylguanidine; Aib, α-aminoisobutyric acid; Cle, cycloleucine (1-
aminocyclpentane-1-carboxylic acid); Acpc, 1-amino-cyclopropane-1-carboxylic acid
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catalyst’s ability to perform a kinetic resolution on mono-coupled
coupling.19 1-Naphthol turned out to be an excellent substrate, such that
product 4a,16 effectively increasing the observed er. In these cases, there
is a correlation between enantioselectivity and the degree of over-
conversion to the bis-coupled product 6a. In order to directly assess the
possibility a of kinetic resolution, we showed that when racemic 4a was
subjected to the reaction conditions employing the tetrapeptide catalyst
derived from L14, a significant krel value of 7.9 was measured (Scheme
1). Indeed, the slow reacting enantiomer in Scheme 1 was found to
match the major enantiomer from the previous experiments, verifying
the presence of a secondary resolution. This result could explain the
higher er values observed for L7 and L8 (Table 2, entries 7 and 8) as
these reactions gave higher yields of 6a. With this in mind, several trials
were run with increased equivalents of nucleophile in an attempt to
increase levels of both overall conversion and er values (see SI).
Interestingly, while no notable increase in er was observed, an
enhancement in yield of the mono coupled product was obtained.17 As
the medium is constantly changing while these reactions proceed, it is
possible that the degree of kinetic resolution in an independent
experiment is mostly a qualitative, rather than a quantitative, indicator
of an additional factor leading to the observed levels of
enantioselectivity.
4k is
1
2
3
4
5
6
7
8
Table 3. O-Nucleophile Substrate Scopea
OH
1.3 equiv
R
Me
Me
Me
Me Me
Me
10 mol% Cu(MeCN)4BF4
20 mol% L14
O
O
O
O
4.0 equiv K3PO4
MeCN, 45 °C, 15 h
F3C
N
N
CF3
F3C
N
N
CF3
H
H
H
H
Br
Br
R
R'
3
O
4, R' = Br
6, R' = R
R =
R"
9
Entry
1
Nucleophile
3% Remainingb
4% Yieldb,c
4a, 71 (68)
6% Yieldb,c
6a, 15 (15)
erd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
10
96:4
94:6
93:7
MeO
OH
2e
16
16
4b, 66 (23)
4c, 61 (41)
6b, 7 (5)
OH
3
6c, 13 (5)
F3C
O2N
OH
OH
4
90
4d, 0
6d, 0
n/a
Scheme 1. Kinetic Resolution of a Racemic mixture of 4a
5
18
2
4e, 53 (45)
4f, 63 (63)
6e, 20 (3)
6f, 32 (23)
92:8
94:6
Me
Me
Me
NC
O
O
OH
Me
Me
6f
Me
F3C
N
N
CF3
k1 = slow
F3C
H
H
N
O
Br
0.5 equiv
MeO
O
O
OH
N
N
CF3
MeO
Me
Me
OH
H
H
Me
O
O
7
5
4g, 67 (66)
6g, 21 (17)
97:3
10 mol% Cu(MeCN)4BF4
20 mol% L14
Br
O
O
MeO
OMe
4.0 equiv K3PO4
MeCN, 45 °C, 15 h
O
6a
F3C
N
N
CF3
*
BocHN
H
H
krel = k2/k1 = 7.9
at 49% conv.
k2 = fast
9
14
4h, 59 (49)
4i, 64 (56)
6h, 7 (6)
6i, 13 (7)
96:4
95:5
LTyr
DTyr
OMe
OH
Br
O
8a
8b
OMe
Racemic Mixture of 4a
OH
*As the absolute stereochemistry is currently unknown, enantiomers were drawn arbitarily.
9
1
4j, 13 (8)
6j, 0
>99:1
O-Nucleophile Substrate scope. With optimized conditions and a
ligand associated with both high levels of conversion and
enantioselectivity in hand, we began to explore the scope of phenols
that could be subjected to effective cross-coupling under these
conditions. An electron rich phenol (Table 3, entry 1; 96:4 er), an
electron neutral phenol (Table 3, entry 2, 94:6 er), and an electron poor
phenol (Table 3, entry 3; 93:7 er) all react smoothly to give products
4a-c with high enantioselectivity. While 4-nitrophenol (Table 3, entry
4) is unreactive, other substitutions are well tolerated. For example, 4-
cyanophenol (Table 3, entry 5) allows 4e to be observed with a 92:8 er
after being produced in 53% yield as well as 3-hydroxypyridine which
gives 4f with excellent enantioselectivity and yield (Table 3, entry 6;
97:3 er, at 63% yield). 4-Bromophenol also proves an interesting
substrate, demonstrating high chemoselectivity, as no coupling is
observed involving the bromine on the 4-bromophenol (Table 3, entry
7; 4g, 67% yield, 97:3 er). Both Boc-L-Tyr-OMe and Boc-D-Tyr-OMe
give comparably high levels of enantioselectivity and reactivity under
the reaction conditions, highlighting a tolerance of different stereo-
chemical arrays on the nucleophile (Table 3, entries 8a and 8b
respectively; 4h, 59% yield, 96:4 er; 4i, 64% yield, 95:5 er). In an
attempt to expand the substrate scope, allyl alcohol was subjected to the
reaction conditions (Table 3, entry 9). While only 13% of the desired
coupled 4j is observed, it is nonetheless obtained with essentially total
enantioselectivity (>99:1 er). We then turned our attention to more
sterically hindered phenols. Notably, palladium-catalyzed reactions
have proven effective for cross-coupling of hindered phenols,18 but
these substrates have remained challenging for Cu-catalyzed cross-
aReported results are the average of two trials. Reaction conditions: 3
(0.2 mmol), nucleophile (1.3 equiv), Cu(MeCN)4BF4 (10 mol %),
peptide (20 mol %), K3PO4 (4.0 equiv), and MeCN (0.8 mL), 45 °C
(except for entry 8, which was performed at 60 °C). bYield was
1
determined using H NMR by comparing to an internal NMR standard
(1,4-bis(trimethylsilyl)benzene). cThe numbers in parentheses are
isolated yields. dEnantiomeric ratios were determined using chiral
HPLC analysis. eProducts could not be isolated by the typical
procedure. The crude mixture was debrominated following procedure 9
to give S12 (see SI). NMR yields were determined before
debromination. fEntry was run at 60 °C
obtained with 97:3 er and in 67% yield (Table 4, entry 1), suggesting
that substitution at the ortho position of the phenolic hydroxyl group
would be well-tolerated. As such, under the presently reported reaction
conditions, both 2-phenylphenol and 2-tert-butylphenol undergo
efficient cross-coupling with high enantioselectivity and only slightly
diminished conversion (Table 4, entries 2 and 3 respectively; 4l, 60%
yield, 97:3 er; 4m, 53% yield, 99:1 er). Even 2,4,6-trimethylphenol
which contains o,o’-substituents undergoes coupling, although with
decreased yields of 4n (33%), but with substantial enantioselectivity
(Table 4, entry 4, 97:3 er). Finally, 2,6-diisopropyl phenol exhibits
similar behavior and 4o is obtained in 18% yield with 96:4 er (Table 4,
entry 5). These levels of enantioselectivity, even for such hindered
substrates at modest levels of conversion, are auspicious for these
demanding couplings.
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Journal of the American Chemical Society
Me
Me
As a prelude to eventual applications in high-complexity molecular
environments, we wondered if guanidinylated peptide-
Table 4: Hindered Phenolsa
Me
1
O
O
2
3
F3C
HN
N
H
N
H
CF3
OH
HO
1.3 equiv
1.3 equiv
R"
Me
Me
O
Br
Me
Me
Me
Me
Me
4s
38% yield
98:2 er
Me
Me
N
4
H
O
O
10 mol% Cu(MeCN)4BF4
10 mol% Cu(MeCN)4BF4
5
6
7
8
20 mol% L14
O
O
O
O
20 mol% L14
(6)
Me
F3C
N
N
CF3
Me
Me
4.0 equiv K3PO4
MeCN, 60 °C, 15 h
H
H
F3C
N
N
CF3
F3C
N
H
N
CF3
Br
Br
4.0 equiv K3PO4
MeCN, 60 °C, 15 h
H
H
H
Br
Br
R
R'
3
O
O
3
O
4, R' = Br
6, R' = R
F3C
N
H
N
H
CF3
R =
R"
N
Br
9
4t
<5% yield
Entry
1
Phenol
3% Remainingb
4% Yieldb,c
4k, 67 (50)
6% Yieldb,c
6k, 14 (9)
erd
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
5
97:3
97:3
based catalysts could display a level of chemoselectivity when multiple
nucleophiles were present. For example, if 4-hydroxybenzylalcohol was
employed as a substrate, total selectivity could be observed at the
phenolic site? As a benchmark, we found that at slightly higher
temperatures (60 °C), benzyl alcohol can be employed as a substrate,
and 4p is isolated in 43% yield with 96:4 er (eq 4). Impressively, when
4-hydroxybenzyl alcohol is subjected to the normal reaction conditions
of Table 4, the phenolic oxygen is found to couple almost exclusively
over the benzyl alcohol, affording the coupled product 4q in 65% yield,
with 96:4 er (eq 5); 4r is not observed in appreciable quantity.
Similarly, when 5-hydroxyindole is employed as the nucleophile, a
highly chemoselective C–O bond forming cross-coupling reaction is
observed such that 4s is observed in 38% yield with 98:2 er (eq 6).
Notably, only trace amounts of 4t are detected by LC/MS, and cannot
be isolated, despite precedent for C–N bond forming Cu-catalyzed
cross-coupling of indoles.20 These results suggest that guanidinylated
peptide ligands could have utility in selective cross-coupling in complex
settings when multiple functional groups are present
Ph
OH
OH
2
7
7
4l, 60 (43)
6l, 15 (14)
6m, 13 (8)
t-Bu
4m, 53 (43)
99:1
97:3
3
4
Me
OH
Me
3
4n, 33 (33)
6n, 14 (6)
Me
i-Pr
OH
i-Pr
5
4
4o, 18 (10)
6o, 0
96:4
aReported results are the average of two trials. Reaction conditions: 3
(0.2 mmol), phenol (1.3 equiv), Cu(MeCN)4BF4 (10 mol %), peptide
(20 mol %), K3PO4 (4.0 equiv.) and MeCN (0.8 mL), 60 °C. bYield was
1
determined using H NMR by comparing to an internal NMR standard
(1,4-bis(trimethylsilyl)benzene). cThe numbers in parentheses are
isolated yields. dEnantiomeric ratios were determined using chiral
HPLC analysis.
Finally, we explored the scope of the enantioselective C-O bond-
forming desymmetrization for a set of alternative diarylmethines (Table
Me
Me
Me
Me Me
5).
As noted in our introduction, venerable diarylmethine
Me
OH
1.3 equiv
desymmetrizations are often reported with limited scope at the pro-
stereogenic center,8-10 and thus it was of considerable interest to explore
this question. We thus examined both conservative and more aggressive
changes to the high-performing substrate 3. As shown in Table 5 (entry
1), symmetrical diarylmethane 3u, bearing additional Cl-substituents,
was found to be an excellent substrate, allowing formation of 4u in 65%
yield with a 95:5 er. As a more “conservative” substrate, this reaction
does reveal important chemoselectivity for enantioselective C-O bond
cross-couplimg at C-Br bonds, rather than C-Cl bonds. In addition,
replacement of the tBu group of 3 with a cyclohexyl substituent (i.e. 3v,
Table 5, entry 2) is reasonably well tolerated, as 4v may be isolated in
O
O
10 mol% Cu(MeCN)4BF4
O
O
20 mol% L14
(4)
F3C
N
H
N
H
CF3
F3C
N
N
CF3
H
H
Br
Br
4.0 equiv K3PO4
MeCN, 60 °C, 15 h
O
Br
3
4p
43% yield
96:4 er
Me
Me
Me
O
O
F3C
N
N
CF3
(5)
H
H
Me
1.3 equiv
HO
OH
Br
O
Me
Me
4q
65% yield
96:4 er
O
O
10 mol% Cu(MeCN)4BF4
57% yield, with
a 91:9 er. Examination of an amide-bearing
OH
20 mol% L14
Me
F3C
N
H
N
H
CF3
Me
Me
diarymethine (3w, Table 5, entry 3) led to a significant decrease in
enantioselectivity, with 4w isolated in modest yield, and 73:27 er.
Compounds with an intervening pyridyl ring (3x) or a TBDPS-ether
(3y) did not undergo enantioselective desymmetrization, however, with
nearly racemic mono-coupled products observed (Table 5, entries 4
and 5). These findings suggest that the catalyst system developed with
ligand L14 allows excellent scope in terms of the phenol coupling
partner, but a more modest – although still significant – scope at the
Br
Br
4.0 equiv K3PO4
MeCN, 60 °C, 15 h
O
O
3
F3C
N
N
CF3
H
H
O
Br
4r
<5% yield
OH
diarylmethine moiety, perhaps at
a level comparable or beyond
previously reported diarylmethine desymmetrizations.
We conclude our results and discussion with an example that harkens
back to our originally stated ambition of remote desymmetrization
during diarylmethane desymmetrization. While many of the examples
above extend the field beyond ortho-functionalization to include many
examples of enantioselective meta-functionalization, with many er
values well into the 90’s, what of the more challenging enantioselective
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Journal of the American Chemical Society
Page 6 of 8
OH
para-functionalization? Such an example was attempted with substrate
Me
Me
Me
Me
1.3 equiv
MeO
Me
Me
1
2
3
4
5
6
7
8
3z (eq 7), with the positions of the Br-atom and the TFA-amide
switched. While compound 3z was prepared, it was found to undergo
the cross-coupling with a low level (59:41 er) of enantioselectivity
under the optimized conditions developed for the more successful
substrates (up to >98:2 er). This observation, while synonymous with a
disappointing outcome, harkens back to our current understanding of
remote asymmetric induction, which seems to be increasing at an
incremental pace.
10 mol% Cu(MeCN)4BF4
20 mol% L14
(7)
Br
Br
O
R
O
R'
O
4.0 equiv K3PO4
MeCN, 60 °C, 15 h
O
NH
CF3
HN
NH
CF3
HN
CF3
CF3
3z
R =
O
4z, R' = Br, 34%, 59:41 er
6z, R' = R, 33%
MeO
Conclusion
In summary, we have reported herein
ligand/Cu-based system for the unusual process of enantioselective C–
O bond forming cross-coupling reactions. A critical feature of the
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5: Diarylmethine Scopea
a
guanidinylated peptide
OH
1.3 equiv
Me
Me
Me
MeO
R2
10 mol% Cu(MeCN)4BF4
system is
a symmetry-breaking reaction of remote sites within
20 mol% L14
O
O
R1
R1
diarylmethine derivatives. At the heart of the selectivity is significant
enantiotopic group differentiation, influenced by the length and
stereochemical array of the peptide ligand, and a modicum of kinetic
resolution that occurs as the product reacts further. A significant scope
of phenolic nucleophiles is also reported that reveals tolerance of a
range of electronically tuned substituents, as well as considerable steric
hindrance. Multifunctional substrates were also demonstrated to
participate in the reaction in a manner that supports the predictable
functionalization of phenols in the presence of other nucleophilic
functional groups, foreshadowing potential applications in complex
molecular settings. The scope of the process with respect to the
symmetrical diarylmethines, under the auspices of guanidinylated
peptide ligand L14, was also examined. Aryl chloride substitution is
found to be inert in the presence of aryl bromides, and steric demands
below that of tBu are well-tolerated at the methine moiety. An
intervening amide presents a somewhat intermediate case, while other
substituents were not compatible with a highly selective outcome. As
an initial status report for this previously unknown, intermolecular
enantioselective cross-coupling process, these findings are encouraging.
Yet, they beg the questions of further ligand development, and deeper
understanding of the general process of remote asymmetric induction,
and even of the diarylmethine topological landscape.
4.0 equiv K3PO4
MeCN, 45 °C, 15 h
F3C
N
N
CF3
H
H
Br
Br
R
R'
3
O
4, R' = Br
6, R' = R
R =
MeO
3% Remainingb 4% Yieldb,c
Entry
Substrate
Me
6% Yieldb,c
erd
Me
Me
Cl
Cl
O
O
17
4u, 65 (61)
6u, 15 (13)
95:5
1
F3C
N
H
N
H
CF3
Br
Br
3u
12
4v, 57 (57)
6v, 20 (9)
91:9
2
O
O
F3C
N
H
N
H
CF3
Br
Br
3v
Me
Me
HN
Me
O
3e
9
4w, 54 (36)
6w, 38 (31)
73:27
O
O
F3C
N
H
N
H
CF3
Br
Br
3w
N
5
4x, 29 (18)
6x, 37 (30)
55:45
4
O
O
ASSOCIATED CONTENT
F3C
N
H
N
H
CF3
Br
Br
Br
3x
Supporting Information: The Supporting Information is available
free of charge on the ACS Publications website. Experimental methods,
characterization of all compounds, and copies of spectra can be found in
the Supporting Information.
OTBDPS
O
O
11
4y, 26 (24)
6y, 13 (10)
54:46
5
F3C
N
H
N
H
CF3
Br
3y
ACKNOWLEDGMENT
aReported results are the average of two trials. Reaction conditions: 3
(0.2 mmol), phenol (1.3 equiv), Cu(MeCN)4BF4 (10 mol %), peptide
(20 mol %), K3PO4 (4.0 equiv.) and MeCN (0.8 mL), 45 ᵒC. bYield was
We are grateful to Dr. Daniel R. Fandrick and Dr. Chris H. Senanayake
(Boehringer-Ingelheim), Dr. Robert A. Singer (Pfizer) and Dr. Craig A.
Parrish and Dr. Shane W. Krska (Merck) for their support and interest
in this research. Primary support for this project came from the
National Institute of General Medical Science of the National Institutes
of Health (GM-068649), for which we are grateful.
1
determined using H NMR by comparing to an internal NMR standard
c
(1,4-bis(trimethylsilyl)benzene.methine). The numbers in parentheses
are isolated yields. dEnantiomer ratios were determined using chiral
e
HPLC analysis. Reaction conditions: 3 (0.05 mmol), phenol (1.3
equiv), Cu(MeCN)4BF4 (20 mol %), peptide (40 mol %), K3PO4 (4.0
equiv.) and MeCN (0.8 mL), 35 °C
AUTHOR INFORMATION
Corresponding Author: scott.miller@yale.edu
REFERENCES
(1) (a) Yang, H.; Yang, X. T.; Tang, W. J. Tetrahedron 2016, 72, 6143-6174; (b)
Choi, J.; Fu, G. C. Science 2017, 356; (c) Tellis, J. C.; Kelly, C. B.; Primer, D.
N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Acc. Chem. Res. 2016, 49,
1429-1439; (d) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev.
2015, 115, 9587-9652.
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Page 7 of 8
Journal of the American Chemical Society
(2) (a) Zhou, F. T.; Cai, Q. Beilstein J. Org. Chem. 2015, 11, 2600-2615; (b) Hu,
N.; Li, K.; Wang, Z.; Tang, W. Angew. Chem. Int. Ed. 2016, 55, 5044-5048.
(3) (a) Zhang, Y.; Wang, Q.; Wang, T.; He, H.; Yang, W.; Zhang, X.; Cai, Q. J.
Org. Chem. 2017, 82, 1458-1463; (b) Yang, W.; Liu, Y.; Zhang, S.; Cai, Q.
Angew. Chem. Int. Ed. 2015, 54, 8805-8808.
(4) Salih, M. Q.; Beaudry, C. M. Org. Lett. 2013, 15, 4540-4543.
(5) (a) Gustafson, J. L.; Sigman, M. S.; Miller, S. J. Org. Lett. 2010, 12, 2794-
2797; (b) Lewis, C. A.; Gustafson, J. L.; Chiu, A.; Balsells, J.; Pollard, D.;
Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J. J. Am. Chem. Soc. 2008,
130, 16358-16365; (c) Lewis, C. A.; Chiu, A.; Kubryk, M.; Balsells, J.;
Pollard, D.; Esser, C. K.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J.
J. Am. Chem. Soc. 2006, 128, 16454-16455.
1
2
3
4
5
6
7
8
9
(6) (a) Cheltsov, A. V.; Aoyagi, M.; Aleshin, A.; Yu, E. C.-W.; Gilliland, T.; Zhai,
D.; Bobkov, A. A.; Reed, J. C.; Liddington, R. C.; Abagyan, R. J. Med. Chem.
2010, 53, 3899-3906; (b) Huang, Z.; Ducharme, Y.; Macdonald, D.;
Robichaud, A. Curr. Opin. Chem. Biol. 2001, 5, 432-438; (c) Kaplan, S. A.;
Roehrborn, C. G.; Rovner, E. S.; Carlsson, M.; Bavendam, T.; Guan, Z. J.
Am. Med. Assoc. 2006, 296, 2319-2328; (d) McRae, A. L.; Brady, K. T. Exp.
Opin. Pharmacother. 2001, 2, 883-892; (e) Messaoudi, S.; Hamze, A.;
Provot, O.; Treguier, B.; De Losada, J. R.; Bignon, J.; Liu, J.-M.; Wdzieczak-
Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. ChemMedChem
2011, 6, 488-497.
(7) Harper, K. C.; Bess, E. N.; Sigman, M. S. Nat. Chem. 2012, 4, 366-374.
(8) (a) Chu, L.; Wang, X.-C.; Moore, C. E.; Rheingold, A. L.; Yu, J.-Q. J. Am.
Chem. Soc. 2013, 135, 16344-16347; (b) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.;
Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460-+; (c) Shi, B.-F.;
Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 4882-
4886.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) Lee, T.; Wilson, T. W.; Berg, R.; Ryberg, P.; Hartwig, J. F. J. Am. Chem. Soc.
2015, 137, 6742-6745.
(10) Saget, T.; Cramer, N. Angew. Chem. Int. Ed. 2013, 52, 7865-7868.
(11) (a) Kim, B.; Chinn, A. J.; Fandrick, D. R.; Senanayake, C. H.; Singer, R. A.;
Miller, S. J. J. Am. Chem. Soc. 2016, 138, 7939-7945. (b) For pioneering
studies of Cu-catalyzed cross-coupling reactions with amino acid-based
ligands, see: Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450-1460.
(12) (a) Saphier, M.; Masarwa, A.; Cohen, H.; Meyerstein, D. Eur. J. Inorg.
Chem. 2002, 1226-1234; (b) Rusonik, I.; Cohen, H.; Meyerstein, D. Dalton.
Trans. 2003, 2024-2028.
(13) See supporting information, Table S1-S6 for full details
(14) Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 6975-
6985.
(15) (a) Miller, S. J. Acc. Chem. Res. 2004, 37, 601-610; (b) Metrano, A. J.;
Abascal, N. C.; Mercado, B. Q.; Paulson, E. K.; Hurtley, A. E.; Miller, S. J. J.
Am. Chem. Soc. 2017, 139, 492-516.
(16) (a) Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; John Wiley &
Sons, Inc.: 2007, p 249-330; (b) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
Adv. Synth. Catal. 2001, 343, 5-26; (c) Schreiber, S. L.; Schreiber, T. S.;
Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525-1529.
(17) See supporting information, Table S12 for full details
(18) (a) Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem.
Int. Ed. 2006, 45, 4321-4326; (b) Aranyos, A.; Old, D. W.; Kiyomori, A.;
Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-
4378; (c) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 3224-3225.
(19) (a) Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75, 1791-1794; (b) Niu,
J.; Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 73, 7814-7817.
(20) (a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
11684-11688; (b) Klapars, A.; Antilla, J. C.; Huang, X. H.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727-7729; (c) Zhu, L.; Cheng, L.; Zhang, Y.;
Xie, R.; You, J. J. Org. Chem. 2007, 72, 2737-2743.
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Abstract Figure
OH
6
R‘
R
R
7
O
O
O
O
[
Cu/peptide]
F3C
N
H
N
H
CF3
F3C
N
H
N
H
CF3
8
Br
Br
O
Br
9
R
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
- Up to 68% yield and 99:1 er
- Intermolecular bond formation
HN
O
O
Me
N
HN
Me
Me
Facile coupling of
hindered phenols
Chemoselectivity for
phenolic nucleophiles
Me
O
R =
O
Li
O
Me2N
Me2N
Me
R1
Me
Me
O
Me
HN
OH
N
H
OH
O
N
HO
O
Peptide Ligand
R2
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